tbuckley/cabot-search huggingface dataset:
SIRT1 activation synergizes with FXR agonism in hepatoprotection via governing nucleocytoplasmic shuttling and degradation of FXR
Authors: Shuang Cui, Huijian Hu, An Chen, Ming Cui, Xiaojie Pan, Pengfei Zhang, Guangji Wang, Hong Wang, Haiping Hao
Journal: Acta Pharmaceutica Sinica B (2022)

Farnesoid X receptor (FXR) is widely accepted as a promising target for various liver diseases; however, panels of ligands in drug development show limited clinical benefits, without a clear mechanism. Here, we reveal that acetylation initiates and orchestrates FXR nucleocytoplasmic shuttling and then enhances degradation by the cytosolic E3 ligase CHIP under conditions of liver injury, which represents the major culprit that limits the clinical benefits of FXR agonists against liver diseases. Upon inflammatory and apoptotic stimulation, enhanced FXR acetylation at K217, closed to the nuclear location signal, blocks its recognition by importin KPNA3, thereby preventing its nuclear import. Concomitantly, reduced phosphorylation at T442 within the nuclear export signals promotes its recognition by exportin CRM1, and thereby facilitating FXR export to the cytosol. Acetylation governs nucleocytoplasmic shuttling of FXR, resulting in enhanced cytosolic retention of FXR that is amenable to degradation by CHIP. SIRT1 activators reduce FXR acetylation and prevent its cytosolic degradation. More importantly, SIRT1 activators synergize with FXR agonists in combating acute and chronic liver injuries. In conclusion, these findings innovate a promising strategy to develop therapeutics against liver diseases by combining SIRT1 activators and FXR agonists.
Circulatory Dynamics: Physiologic Studies.
Authors: Man Tobias
Journal: JAMA (1952)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Loss of AID exacerbates the malignant progression of CLL
Authors: Avery C. Lee, Sai Ravi Pingali, Javier A. Pinilla-Ibarz, Michael L. Atchison, Constantinos Koumenis, Yair Argon, Andrei Thomas-Tikhonenko, Carl De Trez, Chih-Chi Andrew Hu, Chih-Hang Anthony Tang
Journal: Leukemia (2022)

Activation-induced cytidine deaminase (AID) has been implicated as both a positive and a negative factor in the progression of B cell chronic lymphocytic leukemia (CLL), but the role that it plays in the development and progression of this disease is still unclear. We generated an AID knockout CLL mouse model, AID-/-/Eμ-TCL1, and found that these mice die significantly earlier than their AID-proficient counterparts. AID-deficient CLL cells exhibit a higher ER stress response compared to Eμ-TCL1 controls, particularly through activation of the IRE1/XBP1s pathway. The increased production of secretory IgM in AID-deficient CLL cells contributes to their elevated expression levels of XBP1s, while secretory IgM-deficient CLL cells express less XBP1s. This increase in XBP1s in turn leads AID-deficient CLL cells to exhibit higher levels of B cell receptor signaling, supporting leukemic growth and survival. Further, AID-/-/Eμ-TCL1 CLL cells downregulate the tumor suppressive SMAD1/S1PR2 pathway and have altered homing to non-lymphoid organs. Notably, CLL cells from patients with IgHV-unmutated disease express higher levels of XBP1s mRNA compared to those from patients with IgHV-mutated CLL. Our studies thus reveal novel mechanisms by which the loss of AID leads to worsened CLL and may explain why unmutated CLL is more aggressive than mutated CLL.
Linguistic Ability in Early Life and Cognitive Function and Alzheimer's Disease in Late Life
Authors: David A. Snowdon
Journal: JAMA (1996)

<h3>Objective.</h3> —To determine if linguistic ability in early life is associated with cognitive function and Alzheimer's disease in late life. <h3>Design.</h3> —Two measures of linguistic ability in early life, idea density and grammatical complexity, were derived from autobiographies written at a mean age of 22 years. Approximately 58 years later, the women who wrote these autobiographies participated in an assessment of cognitive function, and those who subsequently died were evaluated neuropathologically. <h3>Setting.</h3> —Convents in the United States participating in the Nun Study; primarily convents in the Milwaukee, Wis, area. <h3>Participants.</h3> —Cognitive function was investigated in 93 participants who were aged 75 to 95 years at the time of their assessments, and Alzheimer's disease was investigated in the 14 participants who died at 79 to 96 years of age. <h3>Main Outcome Measures.</h3> —Seven neuropsychological tests and neuropathologically confirmed Alzheimer's disease. <h3>Results.</h3> —Low idea density and low grammatical complexity in autobiographies written in early life were associated with low cognitive test scores in late life. Low idea density in early life had stronger and more consistent associations with poor cognitive function than did low grammatical complexity. Among the 14 sisters who died, neuropathologically confirmed Alzheimer's disease was present in all of those with low idea density in early life and in none of those with high idea density. <h3>Conclusions.</h3> —Low linguistic ability in early life was a strong predictor of poor cognitive function and Alzheimer's disease in late life. (<i>JAMA</i>. 1996;275:528-532)
Diagnosis and Treatment of Depression in Late Life
Authors: Barry D. Lebowitz
Journal: JAMA (1997)

<h3>Objective.</h3> —To reexamine the conclusions of the 1991 National Institutes of Health Consensus Panel on Diagnosis and Treatment of Depression in Late Life in light of current scientific evidence. <h3>Participants.</h3> —Participants included National Institutes of Health staff and experts drawn from the Planning Committee and presenters of the 1991 Consensus Development Conference. <h3>Evidence.</h3> —Participants summarized relevant data from the world scientific literature on the original questions posed for the conference. <h3>Process.</h3> —Participants reviewed the original consensus statement and identified areas for update. The list of issues was circulated to all participants and amended to reflect group agreement. Selected participants prepared first drafts of the consensus update for each issue. All drafts were read by all participants and were amended and edited to reflect group consensus. <h3>Conclusions.</h3> —The review concluded that, although the initial consensus statement still holds, there is important new information in a number of areas. These areas include the onset and course of late-life depression; comorbidity and disability; sex and hormonal issues; newer medications, psychotherapies, and approaches to long-term treatment; impact of depression on health services and health care resource use; late-life depression as a risk factor for suicide; and the importance of the heterogeneous forms of depression. Depression in older people remains a significant public health problem. The burden of unrecognized or inadequately treated depression is substantial. Efficacious treatments are available. Aggressive approaches to recognition, diagnosis, and treatment are warranted to minimize suffering, improve overall functioning and quality of life, and limit inappropriate use of health care resources.
Corrigendum to “The Role of Stereotactic Ablative Body Radiotherapy in Renal Cell Carcinoma” [Eur Urol 2022]
Authors: Muhammad Ali, Jennifer Mooi, Nathan Lawrentschuk, Rana R. McKay, Raquibul Hannan, Simon S. Lo, William A. Hall, Shankar Siva
Journal: European Urology (2022)
Effect of Peritoneal Fixation (PerFix) on Lymphocele Formation in Robot-assisted Radical Prostatectomy with Pelvic Lymphadenectomy: Results of a Randomized Prospective Trial
Authors: Vladimir Student, Zbynek Tudos, Zuzana Studentova, Ondrej Cesak, Hana Studentova, Vaclav Repa, Dana Purova, Vladimir Student
Journal: European Urology (2022)
Genomic Variations in the Tea Leafhopper Reveal the Basis of Its Adaptive Evolution
Authors: Qian Zhao, Longqing Shi, Weiyi He, Jinyu Li, Shijun You, Shuai Chen, Jing Lin, Yibin Wang, Liwen Zhang, Guang Yang, Liette Vasseur, Minsheng You
Journal: Genomics Proteomics & Bioinformatics (2022)

Abstract Tea green leafhopper (TGL), Empoasca onukii, is of biological and economic interest. Despite numerous studies, the mechanisms underlying its adaptation and evolution remain enigmatic. Here, we use previously untapped genome and population genetics approaches to examine how the pest adapted to different environmental variables and thus has expanded geographically. We complete a chromosome-level assembly and annotation of the E. onukii genome, showing notable expansions of gene families associated with adaptation to chemoreception and detoxification. Genomic signals indicating balancing selection highlight metabolic pathways involved in adaptation to a wide range of tea varieties grown across ecologically diverse regions. Patterns of genetic variations among 54 E. onukii samples unveil the population structure and evolutionary history across different tea-growing regions in China. Our results demonstrate that the genomic changes in key pathways, including those linked to metabolism, circadian rhythms, and immune system functions, may underlie the successful spread and adaptation of E. onukii. This work highlights the genetic and molecular basis underlying the evolutionary success of a species with broad economic impacts, and provides insights into insect adaptation to host plants, which will ultimately facilitate more sustainable pest management.
Preclinical safety evaluation and tracing of human mesenchymal stromal cell spheroids following intravenous injection into cynomolgus monkeys
Authors: Cheung Kwan Yeung, Yaping Yan, Li Yan, Yanchao Duan, Enqin Li, Borong Huang, Ke Lu, Koukou Li, Muya Zhou, Lei Zhang, Yaojiong Wu, Kathy Qian Luo, Weizhi Ji, Ren-He Xu, Wei Si
Journal: Biomaterials (2022)
Recommendations for Follow-up Care of Individuals With an Inherited Predisposition to Cancer
Authors: Wylie Burke
Journal: JAMA (1997)

<h3>Objective.</h3> —To provide recommendations for cancer surveillance and risk reduction for individuals carrying mutations in the<i>BRCA1</i>or<i>BRCA2</i>genes. <h3>Participants.</h3> —A task force with expertise in medical genetics, oncology, primary care, gastroenterology, and epidemiology convened by the Cancer Genetics Studies Consortium (CGSC), organized by National Human Genome Research Institute (previously the National Center for Human Genome Research). <h3>Evidence.</h3> —Studies evaluating cancer risk, surveillance, and risk reduction in individuals genetically susceptible to breast and ovarian cancer were identified using MEDLINE (National Library of Medicine) and from bibliographies of articles thus identified. Indexing terms used were "genetics" in combination with "breast cancer," "ovarian cancer," and "screening," or "surveillance" in combination with "cancer family" and "<i>BRCA1</i>" and "<i>BRCA2</i>." For studies evaluating specific interventions, quality of evidence was assessed using criteria of the US Preventive Services Task Force. <h3>Consensus Process.</h3> —The task force developed recommendations through discussions over a 14-month period. <h3>Conclusions.</h3> —Efficacy of cancer surveillance or other measures to reduce risk in individuals who carry cancer-predisposing mutations is unknown. Based on expert opinion concerning presumptive benefit, early breast cancer and ovarian cancer screening are recommended for individuals with<i>BRCA1</i>mutations and early breast cancer screening for those with<i>BRCA2</i>mutations. No recommendation is made for or against prophylactic surgery (eg, mastectomy, oophorectomy); these surgeries are an option for mutation carriers, but evidence of benefit is lacking, and case reports have documented the occurrence of cancer following prophylactic surgery. It is recommended that individuals considering genetic testing be counseled regarding the unknown efficacy of measures to reduce risk and that care for individuals with cancer-predisposing mutations be provided whenever possible within the context of research protocols designed to evaluate clinical outcomes.
Mental Defectives; Their History, Treatment and Training.
Journal: JAMA (1905)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
MAFLD 2022: An ELPA/ALPA/EASO-ECPO joint statement on disease stigma
Authors: Gamal Shiha, Marko Korenjak, Teresa Casanovas, Vicki Mooney, Sólveig Sigurðardóttir, Yiannoula Koulla, Reham Soliman
Journal: Journal of Hepatology (2022)
A Permutation Test-Based Approach to Strengthening Inference on the Effects of Environmental Mixtures: Comparison between Single-Index Analytic Methods
Authors: Drew B. Day, Sheela Sathyanarayana, Kaja Z. LeWinn, Catherine J. Karr, W. Alex Mason, Adam A. Szpiro
Journal: Environmental Health Perspectives (2022)

Background: Optimization of mixture analyses is critical to assess potential impacts of human exposures to multiple pollutants. Single-index regression methods quantify total mixture association and chemical component contributions. Single-index methods include several variants of quantile g-computation (QGC) and weighted quantile sum regression (WQSr), though each has limitations. Objectives: We developed a novel permutation test for WQSr and compared its performance to extant versions of WQSr and QGC in simulation studies and an analysis of prenatal phthalates and childhood cognition. Methods: WQSr uses ensemble nonlinear optimization to identify weights for mixture exposures in an index associated with the outcome in a prespecified direction, with ensembles based on bootstrap resampling (WQSBS) or random subsetting of exposures (WQSRS). Statistical significance can be assessed without splitting the data (Nosplit), by splitting the data into training and test sets (Split), by repeatedly holding out test sets (RH), or by using a novel permutation test (PT) to obtain a more accurate p-value. QGC instead provides a sum mixture coefficient and component coefficients with no constraints on direction. In simulations, we compared false positive rates (FPR) and power to detect true associations and accuracy in estimating mixture weights. We also estimated associations between prenatal phthalate mixtures and childhood IQ in the Conditions Affecting Neurocognitive Development and Learning in Early Childhood cohort using each method. Results: FPR was well controlled at ≤7% in all but the Nosplit WQSr variants. Among these methods, the WQSBS and WQSRS PT variants had the highest power (89%–98%), with lower power for QGC (85%–93%) and RH (60%–97%) or Split WQSr variants (40%–78%). WQSr methods estimated mixture weights 2–4 times more accurately than the QGC method. Coefficients for mixture associations with full scale IQ varied 3- to 4-fold across analytic methods. Discussion: WQSr paired with our novel permutation test best balanced power and false positive rate when assessing a mixture effect. As new methods develop, each should be examined for performance and applicability. https://doi.org/10.1289/EHP10570
Association of Genetic Predisposition and Physical Activity With Risk of Gestational Diabetes in Nulliparous Women
Authors: Kymberleigh A. Pagel, Hoyin Chu, Rashika Ramola, Rafael F. Guerrero, Judith H. Chung, Samuel Parry, Uma M. Reddy, Robert M. Silver, Jonathan G. Steller, Lynn M. Yee, Ronald J. Wapner, Matthew W. Hahn, Sriraam Natarajan, David M. Haas, Predrag Radivojac
Journal: JAMA Network Open (2022)

Polygenic risk scores (PRS) for type 2 diabetes (T2D) can improve risk prediction for gestational diabetes (GD), yet the strength of the association between genetic and lifestyle risk factors has not been quantified.
An Evidence-Based Educational Intervention for Reducing Coercive Measures in Psychiatric Hospitals
Authors: Maritta Välimäki, Tella Lantta, Minna Anttila, Tero Vahlberg, Sharon-Lise Normand, Min Yang
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Investing in health care staffs' education can change the scope of action and improve care. The effectiveness of staff education remains inconclusive. <h3>Objective</h3> To examine whether an evidence-based educational intervention for nurses decreases the use of seclusion rooms in psychiatric hospitals compared with usual practice. <h3>Design, Setting, and Participants</h3> In this pragmatic, 2-arm parallel, stratified cluster randomized clinical trial, 28 wards in 15 psychiatric hospitals in Finland were screened for eligibility and randomly allocated (1:1). Nurses joined on either intervention (n = 13) or usual practice (n = 15) wards. The intervention was performed from May 1, 2016, to October 31, 2017. The follow-up data for January 1 to December 31, 2017, were collected from hospital registers in 2018. Data analysis was performed October 27, 2021. <h3>Interventions</h3> Evidence-based education delivered during 18 months, including 8 months of active education, followed by a 10<b>-</b>month maintenance period. <h3>Main Outcomes and Measures</h3> The primary outcome was the occurrence of patient seclusion (events per total number of patients). <h3>Results</h3> Of 28 psychiatric hospital wards screened (437 beds and 648 nurses), 27 wards completed the study. A total of 8349 patients were receiving care in the study wards, with 53% male patients and a mean (SD) age of 40.6 (5.7) years. The overall number of seclusions was 1209 (14.5%) in 2015 and 1349 (16.5%) in 2017. In the intervention group, the occurrence rate of seclusion at the ward level decreased by 5.3% from 629 seclusions among 4163 patients (15.1%) to 585 seclusions among 4089 patients (14.3%) compared with a 34.7% increase from 580 seclusions among 4186 patients (13.9%) to 764 seclusions among 4092 patients (18.7%) in the usual practice group. The adjusted rate ratio was 0.86 (95% CI, 0.40-1.82) in 2015 and 0.66 (95% CI, 0.31-1.41) in 2017 (<i>P</i> = .003). However, the number of forced injections increased in the intervention group from 317 events among 4163 patients (7.6%) in 2015 to 486 events among 4089 patients (11.9%) in 2017 compared with an increase in the usual practice group from 414 events among 4186 patients (9.9%) in 2015 to 481 events among 4092 patients (11.8%) in 2017. Seven adverse events were reported. <h3>Conclusions and Relevance</h3> In this randomized clinical trial, the educational intervention had a limited effect on the change of occurrence rate of patient seclusion, whereas the use of forced injections increased. More studies are needed to better understand the reasons for these findings. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT02724748
Clonal Hematopoiesis of Indeterminate Potential in Patients with Solid Tumor Malignancies
Authors: Catherine H. Marshall, Lukasz P. Gondek, Jun Luo, Emmanuel S. Antonarakis
Journal: Cancer Research (2022)

Clonal hematopoiesis of indeterminate potential (CHIP) refers to the expansion of cells of hematopoietic lineage that carry acquired somatic alterations associated with hematologic malignancies. The most commonly altered genes giving rise to CHIP are DNMT3A, TET2, and ASXL1. However, advanced sequencing technologies have resulted in highly sensitive detection of clonal hematopoiesis beyond these known driver genes. In practice, CHIP is commonly identified as an incidental finding in liquid and tissue biopsies of patients with solid tumors. CHIP can have broad clinical consequences, given its association with hematologic malignancies and nonmalignant diseases. CHIP can also interfere with next-generation DNA sequencing results, so clinicians should pay careful attention when these results are being used to guide therapy. Future research is needed to determine how solid tumor malignancies and their treatments alter the progression of CHIP, and in turn, how CHIP might be used to improve treatment selection and outcomes for patients with solid tumors.
Hypoxia and low temperature upregulate transferrin to induce hypercoagulability at high altitude
Authors: Meiquan Li, Xiaopeng Tang, Zhiyi Liao, Chuanbin Shen, Ruomei Cheng, Mingqian Fang, Gan Wang, Ya Li, Shuzhen Tang, Li Xie, Zhiye Zhang, Peter Muiruri Kamau, James Mwangi, Qiumin Lu, Yaxiong Li, Yuming Wang, Daniel Thomas MacKeigan, Eric G. Cerenzia, Heyu Ni, Ren Lai
Journal: Blood (2022)

Studies have shown significantly increased thromboembolic events at high altitude. We recently reported that transferrin could potentiate blood coagulation, but the underlying mechanism for high altitude-related thromboembolism is still poorly understood. Here, we examined the activity and concentration of plasma coagulation factors and transferrin in plasma collected from long-term human residents and short-stay mice exposed to varying altitudes. We found that the activities of thrombin and factor XIIa (FXIIa) along with the concentrations of transferrin were significantly increased in the plasma of humans and mice at high altitudes. Furthermore, both hypoxia (6% O2) and low temperature (0°C), 2 critical high-altitude factors, enhanced hypoxia-inducible factor 1α (HIF-1α) levels to promote the expression of the transferrin gene, whose enhancer region contains HIF-1α binding site, and consequently, to induce hypercoagulability by potentiating thrombin and FXIIa. Importantly, thromboembolic disorders and pathological insults in mouse models induced by both hypoxia and low temperature were ameliorated by transferrin interferences, including transferrin antibody treatment, transferrin downregulation, and the administration of our designed peptides that inhibit the potentiation of transferrin on thrombin and FXIIa. Thus, low temperature and hypoxia upregulated transferrin expression-promoted hypercoagulability. Our data suggest that targeting the transferrin-coagulation pathway is a novel and potentially powerful strategy against thromboembolic events caused by harmful environmental factors under high-altitude conditions.